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Older patients with chronic kidney disease (CKD) had greater risks for serious adverse events when starting on low-dose methotrexate rather than hydroxychloroquine, a propensity score-matched analysis found.

About 60% of the cohort's new prescription came from a rheumatologist. Within 90 days of starting either treatment, the risk for the composite outcome -- a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects -- doubled with low-dose methotrexate versus hydroxychloroquine (3.55% vs 1.73%; risk ratio 2.05, 95% CI 1.42-2.96), according to researchers led by Flory T. Muanda, MD, PhD, of Western University in London, Ontario.

And patients' risks only increased as their estimated glomerular filtration rate (eGFR) declined, the group wrote in .

"It is crucial to actively monitor these patients with regular blood tests and chest x-rays to detect signs of myelosuppression, infection, hepatotoxicity, and pneumotoxicity," Muanda told MedPage Today. "If the risks outweigh the benefits, prescribers should prioritize using other disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine."

He advised clinicians that it's "essential to balance the risks and benefits" when using methotrexate in CKD patients. If indeed the benefits do outweigh the risks, then these patients should be started on an even lower dose -- between 5 mg to less than 15 mg/week.

The FDA and Health Canada "should also consider issuing warning labels to inform prescribers of the study's findings," the researchers wrote.

Methotrexate is commonly prescribed for rheumatoid arthritis, psoriasis, and Crohn's disease, but is also prescribed off-label for dermatomyositis, eczema, systemic lupus erythematosus, and systemic sclerosis. Risks with this DMARD can be higher for patients with CKD because it is eliminated via the kidneys. For the study, hydroxychloroquine was selected as a comparator given some of its overlapping indications (rheumatoid arthritis, lupus, dermatomyositis).

When the composite primary endpoint was broken down, the highest increased risk appeared to be for a hospital visit with myelosuppression (RR 4.40, 95% CI 1.73-11.20), followed by pneumotoxic effects (RR 2.28, 95% CI 1.43-3.63), and all-cause hospitalization (RR 1.39, 95% CI 1.13-1.69); risk for sepsis-related hospitalization or all-cause mortality was not significantly higher.

Myelosuppression, serious infections, and hepatotoxic effects are some of the serious adverse events known to be associated with low-dose methotrexate, and while little information existed as to whether these risks were "amplified" in patients with CKD, Muanda said he wasn't particularly surprised by these findings.

"A pharmacokinetic study showed that methotrexate clearance was slower in patients with lower levels of creatinine clearance, and its half-life was twofold higher in patients with a creatinine clearance <45 mL/min compared to those with a creatinine clearance >80 mL/min," he explained. "In other words, patients with low kidney function had a higher methotrexate half-life elimination than those with normal kidney function."

"Over 50 case reports of patients with CKD suggest that the risk of toxicity with low-dose methotrexate (5-35 mg/week) was substantial in these high-risk populations," Muanda added.

For this study, researchers looked at eight Canadian administrative healthcare databases. The cohort included adults with CKD ages 66 and older with an eGFR less than 60 mL/min/1.73 m², excluding patients receiving dialysis and kidney transplant recipients. Most were women with an eGFR between 45-59, and over half were being treated for rheumatoid arthritis.

A total of 2,309 patients newly dispensed oral methotrexate from an outpatient pharmacy between 2008 and 2021 were matched with 2,309 patients dispensed hydroxychloroquine. Low-dose oral methotrexate was considered between 5 to 35 mg/week and oral hydroxychloroquine ranged from 200 to 400 mg/day.

In a secondary analysis, researchers separated out two methotrexate groups -- those who started at 15 to 35 mg/week and those who took 5 to <15 mg/week -- and compared them with hydroxychloroquine users. The association with serious adverse events was dose-dependent, as those who started on the higher methotrexate dose had a 3.25-times greater risk for the composite outcome compared with hydroxychloroquine users, while those who started on the lower dose did not have an elevated risk.

Muanda's group pointed out that this study results may not apply to CKD patients under 66. Risk-benefit ratio also wasn't quantified, and the study was likewise limited by an underestimation of adverse events that didn't result in hospital visits.

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